PROJECT SUMMARY Influenza virus is a significant pathogen in pediatric solid organ transplant (SOT) patients. However, these individuals respond poorly to standard-dose (SD) inactivated influenza vaccine (IIV). Recent studies have investigated two strategies to overcome poor immune responses in SOT recipients: administration of high-dose (HD)-IIV compared to SD-IIV or two doses of SD-IIV compared to one dose of SD-IIV in the same influenza season. A phase 1 trial of HD-IIV vs. SD-IIV in pediatric SOT was safe, and suggested higher immunogenicity. In a phase II trial of adult SOT recipients, single-dose HD-IIV revealed increased immunogenicity compared to single-dose SD-IIV. However, the administration of two-doses of HD-IIV in the same influenza season has not been evaluated in either adult or pediatric SOT. Also, the vast majority of SOT influenza vaccinations studies have not substantively evaluated prolonged immunogenicity into the following influenza season. Importantly, prior influenza vaccine studies of pediatric SOT recipients have enrolled few subjects immunized within the early (<24 month) post-transplantation period. Therefore, the optimal immunization strategy for pediatric SOT recipients less than 24 months post-transplant is poorly-defined. Finally, immunologic predictors and correlates of influenza vaccine immunogenicity in pediatric SOT have not been defined. We hypothesize that two doses of HD-IIV will be more immunogenic compared to two doses of SD-IIV in pediatric SOT recipients as evident by higher hemagglutination inhibition (HAI) titer antibody responses to influenza A antigens. To test this hypothesis and address the above critical knowledge gaps, we propose to conduct a phase II multicenter randomized controlled trial (RCT) of two doses HD-IIV compared to two doses of SD-IIV in the first two years following pediatric heart, kidney, or liver transplantation. The results of this study will address significant gaps in knowledge regarding influenza vaccine strategies and immune responses in pediatric SOT and will guide vaccine recommendations in this vulnerable population. To ensure a successful trial, we propose the present R34-supported preparatory phase. During the R34 period, we will finalize the trial protocol, statistical analysis plan, and data management plan, and will submit the protocol to the FDA for an investigational new drug application. The second emphasis area for the R34 period is to finalize selection of currently identified study sites and prepare each site for rapid identification and enrollment of study subjects. Development of this subject recruitment plan for each site is essential for an efficient and successful trial given the limited time window that exists seasonally prior to standard-of-care influenza vaccination receipt. Finally, we will work closely with our laboratory cores (T-cell, B-cell, and HLA immunology cores) to optimize sample collection and utilization plans to ensure our ability to comprehensively assess influenza vaccine immunogenicity and identify immunologic predictors and correlates of influenza vaccine immunogenicity.